Induction of apoptosis in human T-cells by methyl mercury: Temporal relationship between mitochondrial dysfunction and loss of reductive reserve
Induction of apoptosis in human T-cells by methyl mercury: Temporal relationship between mitochondrial dysfunction and loss of reductive reserve
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DOI：
10.1006/taap.1999.8652
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发表时间：
1999-05-15
影响因子：
3.8
通讯作者：
Shpiro, IM
中科院分区：
文献类型：
--
作者：
Shenker, BJ;Guo, TL;Shpiro, IM
本研究的目的是确定氯化甲基汞诱导人T细胞凋亡的机制。我们提出了这样一个问题：汞是否会破坏Δ psi（m）并诱导线粒体通透性过渡态？使用两种荧光试剂JC-1和DiOC（6）（3），我们证明了MeHgCl暴露导致Delta psi（m）降低。由于Δ psi（m）的下降会干扰pH（i），我们采用SNARF-1评估pH（i）;结果表明汞处理将pH（i）从7.0降低至6.5。与这些观察结果一致，我们注意到，非偶联电子转移反应产生ROS，而心磷脂，线粒体磷脂，被氧化。在音乐会的生化变化，有一个整体尺寸的汞处理的细胞的线粒体和嵴结构的损失减少。毒物还耗尽了细胞的巯基储备，并促进细胞色素c从线粒体到胞质溶胶的易位。此外，当T细胞巯基耗尽，有增加的易感性MeHgCl诱导的细胞凋亡。最后，我们建立了Delta psi（m）下降、ROS生成和巯基储备消耗之间的时间关系。最早可检测到的事件是在线粒体水平;在MeHgCl存在下，线粒体Delta psi（m）显著降低，GSH水平在1小时内下降。随后，巯基储备的进一步减少与ROS的产生有关。我们建议，氯化甲基汞的目标细胞器是细胞器和氧化应激的诱导导致死亡信号通路的激活。(C)北京：科学出版社.
The objective of our study was to define the mechanism by which MeHgCl induces human T-cell apoptosis. We asked the question: does mercury disrupt the Delta psi(m) and induce a mitochondrial permeability transition state? Using two fluorescent reagents, JC-1 and DiOC(6)(3), we demonstrated that MeHgCl exposure resulted in a decrease in the Delta psi(m). Since a decline in Delta psi(m) can disturb the pH(i), we employed SNARF-1 to assess pH(i); results indicate that mercury treatment reduced the pH(i) from 7.0 to 6.5. Consistent with these observations, we noted that uncoupled electron transfer reactions generated ROS, while cardiolipin, a mitochondrial phospholipid, was oxidized. In concert with the biochemical changes, there was a decrease in overall dimension of the mitochondria of mercury-treated cells and a loss in cristae architecture. The toxicant also depleted the thiol reserves of the cell and promoted translocation of cytochrome c from the mitochondria to the cytosol. Furthermore, when T cells were thiol-depleted, there was increased susceptibility to MeHgCl-induced apoptosis. Finally, we established a temporal relationship between the decline in Delta psi(m), generation of ROS, and depletion of thiol reserves. The earliest detectable event was at the level of the mitochondrion; in the presence of MeHgCl there was a profound reduction in mitochondrial Delta psi(m), and a decline in GSH levels within 1 h. Subsequently, a further decrease in thiol reserves was linked to the generation of ROS. We propose that the target organelle for MeHgCl is the mitochondrion and that induction of oxidative stress leads to activation of death-signaling pathways. (C) 1999 Academic Press.